期刊
PLOS ONE
卷 7, 期 10, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0046823
关键词
-
资金
- National Institute of Health NCI [5K01CA115681]
- TGen-VARI Integration Grant
- Howard Hughes Medical Institute through the Undergraduate Science Education Program
- Helios Education Foundation
- Cancer League of Basel Fellowship Grant
- Basic Medical Sciences department
- Dean's Office at the University of Arizona College of Medicine-Phoenix
Nuclear Factor kappa B (NF-kappa B) is a key mediator of normal immune response but contributes to aggressive cancer cell phenotypes when aberrantly activated. Here we present evidence that the Inhibitor of Growth 4 (ING4) tumor suppressor negatively regulates NF-kB in breast cancer. We surveyed primary breast tumor samples for ING4 protein expression using tissue microarrays and a newly generated antibody. We found that 34% of tumors expressed undetectable to low levels of the ING4 protein (n = 227). Tumors with low ING4 expression were frequently large in size, high grade, and lymph node positive, suggesting that down-regulation of ING4 may contribute to breast cancer progression. In the same tumor set, we found that low ING4 expression correlated with high levels of nuclear phosphorylated p65/RelA (p-p65), an activated form of NF-kappa B (p = 0.018). Fifty seven percent of ING4-low/p-p65-high tumors were lymph node-positive, indicating a high metastatic tendency of these tumors. Conversely, ectopic expression of ING4 inhibited p65/RelA phosphorylation in T47D and MCF7 breast cancer cells. In addition, ING4 suppressed PMA-induced cell invasion and NF-kappa B-target gene expression in T47D cells, indicating that ING4 inhibited NF-kappa B activity in breast cancer cells. Supportive of the ING4 function in the regulation of NF-kappa B-target gene expression, we found that ING4 expression levels inversely correlated with the expression of NF-kappa B-target genes in primary breast tumors by analyzing public gene expression datasets. Moreover, low ING4 expression or high expression of the gene signature composed of a subset of ING4-repressed NF-kappa B-target genes was associated with reduced disease-free survival in breast cancer patients. Taken together, we conclude that ING4 negatively regulates NF-kappa B in breast cancer. Consequently, down-regulation of ING4 leads to activation of NF-kappa B, contributing to tumor progression and reduced disease-free patient survival in breast cancer.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据